The present invention relates to a method of fluorescence diagnosis of tissue, particularly by endoscopy, as well as devices for performing fluorescence diagnoses. Such devices are also referred to as photodynamic diagnosis systems (PDD systems).
These methods or devices, respectively, are employed for the xe2x80x9cin vivoxe2x80x9d diagnosis operating on a reaction induced by light in biologic tissue by an endogenic or exogenic photo sensitising agent; such methods and devices can be employed in particular for the (early) diagnosis of tumours and for tumour localisation.
Fundamentals
For triggering a light-induced reaction in biologic systems a photo sensitising agent (also referred to as photo sensitizer) can be administered to the patient in a concentration of a few mg/kg of the body weight. Typical photo sensitizers display a basic hemato-porphyrin structure such as the substances Photofrin and Photosan-3. Another photo sensitizer that is frequently used in urology and dermatology is delta amino levulinic acid (ALA).
The hemato-porphyrin derivatives are administered into the veins whereas delta amino levulinic acid is suitable for local application, which means that it is injected as a solution into the urinary bladder. These substances accumulate in tumour tissues in a concentration increased by 2 to 10 times. This selective accumulation in the tumour tissue constitutes the decisive basis for diagnosing tumours by photo dynamic diagnosis and for the photo dynamic tumour therapy.
For diagnosis, the tissue to be examined is exposed to ultraviolet irradiation for roughly 2 to 12 hours after administration of the photo sensitizer. The photo-sensitising agents present in the tumour tissue in an increased concentration are stimulated by this light and present thereafter a typical red fluorescence by which the tumour can be localised.
In addition to fluorescencexe2x80x94induced by a photo sensitizer accumulated in the tissuexe2x80x94also the so-called auto fluorescence can be triggered in the tissue, which is brought about by so-called fluorophores, i.e. endogenic fluorescent substances.
The bio-physical sequence of light-induced reaction can be assumed to develop as follows:
The photo sensitizer accumulated in the tissue is caused to switch over into an excited state by the absorption of a light quantum carrying a defined energy, which is emitted by the respective light source. Exposure to violet light as part of the photo dynamic diagnosis causes the emission of a fluorescent radiation when the sensitizer returns into the basic state.
In the case of photo dynamic therapy in combination with irradiation with red light at a high power density the transition takes place from the excited state into a meta stable interim state from which the energy that is discharged by the return into the basic state is transferred to molecular oxygen which receives this energy and forms thereby stimulated singlet oxygen. The aggressive singlet oxygen destroys cell structures in the respective tissue by photo oxidation. This cellular damage, together with a simultaneously occurring collapse of the tumour vessel system, results in a complete destruction of the tumour (photo toxic effect).
Prior Art
A method and a device which the wording of the independent Patent Claims starts out from is known from the document WO 97/11636 or the pamphlet xe2x80x9cEndoworld D-Lightxe2x80x9d by Karl Storz GmbH and Co.
PDD systems of another general type are disclosed in the German Patent DE-A41 33 493 or the U.S. Pat. No. 5,701,903. Moreover, the realisation of an endoscopic photo dynamic diagnosis and therapy by means of a device has been proposed wherein a laser, specifically a krypton ion laser, is employed as light source emitting a wavelength of roughly 420 nm and producing a power of more than 200 mWatt. The light of this laser is passed via an optical quartz guide having a numerically small aperture through an endoscope to the locations in the human body which are to be irradiated.
For an explanation of all particulars not described here in details explicit reference is made, by the way, to the aforementioned prior art documents.
The xe2x80x9cD-Light systemxe2x80x9d described in the aforementioned pamphlet has been designed for application with 5-amino levulinic acid (5-ALA) as photo sensitizer also for the induced fluorescence analysis.
For such an application the device comprises an illuminating system including at least one illuminating light source which emits a stimulating light over a wide bandwidth for stimulating the fluorescence of the photo sensitizer. The light is coupled into the optical guide of an endoscope including a lens with an object field illuminated by the stimulating light, and an image transmitting system which transmits the image from the lens to the proximal end of the endoscope. Moreover, a filter system is provided that comprises stimulating filters in the light path between the illuminating system and the tissue to be examined, as well as observation filters along the path of the observation beams, as formed by the lens and the image transmitting system. The characteristics of the stimulating filter in transmission are so selected that the spectral distribution of the stimulating light is matched with the fluorescence stimulating spectrum of the tissue to be examined. The transmission characteristics of the observation filter are so selected that, on the one hand, the fluorescent light is not outshone by the stimulating light reflected on the tissue directly but that, on the other hand, the area under examination can also be observed by the examining physician also due to the directly reflected stimulating light.
The known PDD system xe2x80x9cD-Lightxe2x80x9d has been applied in urology, neuro surgery and other branches for photo dynamic diagnosis with great success.
On the other hand, lung cancer is the most frequently occurring cause of death due to cancer. Attempts have been made to administer the photo sensitizer 5-ALA by inhalation. This furnishes good results only partly. What is particularly problematic is the reproducibility of this form of administration. In accordance with the invention, now the fact has been detected that this problem can be overcome by the simultaneous detection of auto fluorescence.
All the methods in which fluorescence is induced by means of a photo sensitizer suffer from the further advantage that preliminarily the photo sensitizer(s) must be administered for producing its or their effects only after a certain timexe2x80x94within the range from several minutes to a couple of hoursxe2x80x94which, on the other hand, is (are) bleached out in the course of the examination and might also be intolerable under certain conditions.
For this reason methods have been proposed which utilise only the auto fluorescence of tissue. Appropriate systems are disclosed, for instance, in the European Patent EP-B-0 512 965, the U.S. Pat. No. 5,507,287, the U.S. Pat. No. 5,413,108, or the German Patent DE-A-196 461 776. What is a disadvantage in these methods is the aspect that they employ merely the auto fluorescence effect for diagnosisxe2x80x94even though they are comparatively expensivexe2x80x94and hence furnish a comparatively low-contrast image in many cases.
All the aforementioned systems share the common feature that the filter systems provided in the path of the illuminating beams or the observation beams, respectively, are matched with the type of the respective fluorescence to be stimulated. As a consequence, it is necessary to change the filters when fluorescence is stimulated by means of another photo sensitizer or when a change is to be made from fluorescence induced by a photo sensitizer or auto fluorescence.
The present invention is based on the problem of providing a method of endoscopic fluorescence diagnosis of tissue, which permits the execution of different diagnostic proceduresxe2x80x94i.e. diagnostic procedure operating on different photo sensitizers and/or of induced and endogenic fluorescence; moreover, the inventive device should be so designed that the expenditure incurred by a conversion of the device to different diagnostic procedures will be reduced against known devices.
Inventive solutions to this problem are defined in the independent Patent Claims. Improvements of the invention are the subject matters of the dependent Claims.
In accordance with the invention the transmission characteristics of the stimulating filter or filters are so selected that on account of its spectral distribution the stimulating light is able to stimulate at least two different fluorescence modes in the tissue without switching the stimulating filters. The light emitted from the illuminated or irradiated tissue, respectively, due to the at least two different fluorescence modes is selectively observed:
It is possible, for instance, to detect the light, that is emitted from the tissue, as a function of the wavelength; in this approach the followingxe2x80x94exemplary and not limitingxe2x80x94procedure is conceivable:
1. Initially, the light emitted from the tissue in one or several wave length bands is detectedxe2x80x94if applicable with inclusion of auto fluorescence.
2. After administration of one or several photo sensitizer(s) the way is detected in which the emission varies within the wave length bands typical of the fluorescence of these photo sensitizers.
3. In this method it is possible to detect in particular the variation of the emission in this wave length band as a function of time after administration of the photo sensitizer(s).
4. If applicable, upon administration of further photo sensitizers emitting preferably in another wave length band and/or collecting in tissue of a different nature, the variation in emission (possibly over its development versus time) and/or the emission in the respective wave length bands is detected.
5. The condition of the respective irradiated tissue is determined on the basis of the differential signals between the individual emissions and/or the added signals in the individual emission bands, and tumour diagnosis is performed in particular.
It is also possiblexe2x80x94instead of the (not necessarily) simultaneous stimulation of (at least) two fluorescence modes stimulated by two photo sensitizersxe2x80x94to stimulate (at least) one fluorescence mode stimulated by a photo sensitizer and (at least) one endogenic fluorescence mode and/or at least two endogenic fluorescence modes.
In the alternative at least one observation filter is provided for each of the fluorescence modes that can be stimulated, with the transmission characteristics of the filter(s) being matched with the respective fluorescence mode. With such an inventive device it is hence possible to stimulate at least two fluorescence modes simultaneously. The images associated with the respective fluorescence modes are separated by the appropriately structured filters in the path of the observation beam. The images can be processed, for instance in an image processing system, in an additive or subtractive form and/or be compared against the xe2x80x9cstandard imagexe2x80x9d on the basis of the directly reflected light.
In another alternative the transmission characteristics of the observation filter system, which may be composed of several filters if necessary, are so selected that all fluorescence modes which can be simulated may be observed simultaneously, without any change of the filterxe2x80x94possible in different or additional detection channels.
When the images obtained with the individual fluorescence modes are separated the observation filters for the individual fluorescence modes may be inserted successively into the observation beam path; it is also possible to arrange the individual filters in different partial beam paths.
In such a case the two partial beam paths may be formed, for instance, by performing a proximal splitting by means of a beam splitter which may be selective in terms of wave lengths in particular.
Moreover, the endoscope may be a stereo endoscope in which the different filters are provided in the stereo channels.
In the first case, it is preferable to provide a central filter-switching device for the observation filters because then the physician""s attention will not be distracted by a comparatively complex switching procedure.
The switching device may be part of a communication system between the endoscope with filter changing device, the illuminating light source(s) and the video image receiver(s).
In all other respects, the device may be configured in a manner known per se.
It is possible, for example, that the image transmitter system transmits the image of the lens opticallyxe2x80x94e.g. via relay lens systems or imaging fibre bundlesxe2x80x94to the proximal end of the endoscope. On the proximal end at least one video image receiver may be provided for receiving the proximal image of the image transmission system.
In an alternative, the image transmission system may comprise at least one distally disposed video image recorder for recording the image of the lens. In this case the image is xe2x80x9celectricallyxe2x80x9d transmitted, i.e. by the transmission of the signals from the at least one image recorder.
It is preferred in any case that the device is suitable for application also for conventional diagnostic or treatment procedures, i.e. procedures not operating on fluorescence. To this end it is expedient that at least the observation filters can be removed from the observation beam path.
In another preferred embodiment of the invention the observation filters produce such an optical effect that they correct the chromatic aberration of the observation beam path.